# NM_001368809.2(AMPD2):c.971G>C (p.Arg324Pro)

https://sugi.bio/variant/ampd2-p-arg324pro

## Summary

**AMPD2 p.Arg324Pro (c.971G>C)** is classified **Likely pathogenic** in AMPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2013-11-21). AlphaMissense: likely pathogenic (0.9993); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs746332433 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the AMPD2 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AMPD2](https://sugi.bio/atlas/gene/AMPD2/) |
| Protein change (HGVS p.) | p.Arg324Pro |
| Coding change (HGVS c.) | c.971G>C |
| MANE Select transcript | [NM_001368809](https://www.ncbi.nlm.nih.gov/nuccore/NM_001368809) |
| dbSNP | [rs746332433](https://www.ncbi.nlm.nih.gov/snp/rs746332433/) |
| Variant type | single nucleotide variant |
| Location | chr1:109627794-109627794 (GRCh38) |
| ClinVar | [VCV224991](https://www.ncbi.nlm.nih.gov/clinvar/variation/224991/) |

**All HGVS expressions:** `NC_000001.10:g.110170416G>C`, `NC_000001.11:g.109627794G>C`, `NG_034075.1:g.12982G>C`, `NM_001257361.2:c.779G>C`, `NM_001308170.1:c.908G>C`, `NM_001368809.2:c.971G>C`, `NM_004037.9:c.971G>C`, `NM_139156.4:c.890G>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9993) — concordant with the pathogenic call
- REVEL 0.956 (strongly pathogenic-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this damaging; SaProt makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.23) — consistent with the pathogenic call
- Conservation: phyloP 11.891, GERP 2.1, phastCons 1 — highly conserved (agrees)
- **SaProt:** withheld — SaProt scored this protein on a different isoform than AlphaMissense numbered the variant on, and the two diverge from residue 5, so a score under this position number would describe a different residue.
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **R378P** vs ClinVar **R324P**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in AMPD2 (of 5,188 modeled).
- CADD: **PHRED 34.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.44** across the covering region of the MANE Select transcript (109,627,514–109,628,139), spanning 625 bp. Chi-square p 2.1e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.23**, donor gain **0.00**. Largest is acceptor gain, 8 bp away.
  These are **raw** scores. Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — can legitimately show 0 where this shows a score; the masked figures are not available for this record.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,970 in the highest group · 1/1,613,948 alleles overall — very rare (popmax 8.47e-05%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**AMPD2** population constraint: LOEUF 0.705, pLI 1.3901e-08, missense-Z 3.6393. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.28, 59% of residues very-high.

**5 experimental structure(s)** (PDB): [26XC](https://www.rcsb.org/structure/26XC), [4NO3](https://www.rcsb.org/structure/4NO3), [4NO5](https://www.rcsb.org/structure/4NO5), [8HU6](https://www.rcsb.org/structure/8HU6), [8HUB](https://www.rcsb.org/structure/8HUB).

## What this gene does {#gene-function}

*Describes the biological roles of AMPD2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** AMPD2's established molecular role includes AMP deaminase activity.


### Pathways affected {#pathways}

AMPD2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Purine salvage](https://reactome.org/content/detail/R-HSA-74217) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** AMP deaminase activity, identical protein binding.

**Biological process:** IMP biosynthetic process, GMP salvage, cyclic purine nucleotide metabolic process, energy homeostasis.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2013-11-21.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2013-11-21 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related AMPD2 variant pages (same residue, condition, or type): [AMPD2 p.Arg324Leu](/variant/ampd2-p-arg324leu), [AMPD2 p.Arg324Trp](/variant/ampd2-p-arg324trp), [AMPD2 c.-150G>A](/variant/ampd2-c-minus-150g-a), [AMPD2 c.-18G>T](/variant/ampd2-c-minus-18g-t), [AMPD2 p.Ala425=](/variant/ampd2-p-ala425), [AMPD2 p.Arg156Gln](/variant/ampd2-p-arg156gln), [AMPD2 p.Arg163Gln](/variant/ampd2-p-arg163gln), [AMPD2 p.Arg386Trp](/variant/ampd2-p-arg386trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 224991). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*